Lovastatin and its analogs, e.g., simvastatin, are potent antihyper-cholesterolemic agents that function by limiting cholesterol biosynthesis by inhibiting the enzyme HMG--CoA reductase. These compounds, which may be referred to generally as statins, are known to exist in open ring hydroxy acid and also in lactone form. The lactone form and the hydroxy acid form of these compounds have the following general structural Formulas: ##STR1## wherein Z is hydrogen, a metal cation, such as sodium or potassium, or NH.sub.4, and R is ##STR2## wherein R.sub.1 is H or CH.sub.3.
The open hydroxy acid form of the statins (Formula II) is the one which is biologically active. However, the statins are generally administered to a patient in the lactone form (Formula I), which is converted to its active metabolite, the hydroxy acid form, in the body.
In the process of manufacture of lovastatin and its analogs, e.g., simvastatin, the lactonization of free hydroxy acid or its salt to lactone form constitutes an essential step.
Processes known in the literature for the lactonization of the free, hydroxy acid or its salts are either carried out under drastic heat conditions, i.e., refluxing with inert solvents, or catalyzed by strong acids when lactonization is effected at ambient temperature. The process disclosed in U.S. Pat. No. 4,820,850 involves heating the free acid or its salt, e.g., the ammonium salt, to reflux temperature (usually 100-110.degree. C.) in high boiling hydrocarbon solvents such as toluene for 7-8 hours. The ambient acidity of the acid is believed to be responsible for the lactonization reaction at these high temperatures. In addition, water which is formed as a by-product of the reaction is continuously removed by azeotropic distillation, which forces the reaction to near completion. The process of lactonization under heat conditions of reflux temperatures is complicated by the formation of many impurities, of which dimer formation especially lowers the quality of the final lactone product. The dimer is a difficult-to-remove impurity and is present at the levels of 0.4 to 0.8% in the product. In order to minimize the dimer impurity, high dilutions are often used in the lactonization reaction at the cost of the efficiency of the reaction and of the process, which is disadvantageous at a commercial manufacturing scale.
U.S. Pat. No. 4,916,239 discloses another process wherein the lactonization reaction is carried out at room temperature by treating the free hydroxy acid ammonium salt of a mevinic acid in a mixture of acetic acid and water, and in the presence of a strong acid catalyst. After the free hydroxy acid-lactone equilibrium is established (reaction has proceeded to 50% conversion), water is gradually added in lots to effect crystallization of the lactone from the reaction medium. This removal of lactone continuously shifts the equilibrium to the lactone side thus leading to reaction completion. This process suffers from several disadvantages and is also not convenient to operate at a large scale for a variety of reasons, some of which are discussed below
Use of a strong mineral or an organic acid catalyst, e.g., formic, phosphoric, trifluoroacetic, sulphuric, hydrochloric, p-toluene sulphonic, methanesulphonic acids, etc., in quantities varying from 1.2 to 1.5 molar equivalents makes this process hazardous and environmentally unacceptable on an industrial scale. The excess acid catalyst which is used needs to be neutralized by adding a strong base before filtration of the product.
Furthermore, the lactonization reaction is only about 50% complete after the equilibrium is achieved. At this point of time, any fast or premature addition of water can lead to serious crystallization and filtration problems. Moreover, reaction and subsequent workup takes about 9-12 hours for completion, thereby decreasing the efficiency of the process.
The above-mentioned disadvantages make the process of U.S. Pat. No. 4,916,239 operationally tedious, inefficient, expensive and environmentally hazardous on an industrial scale.